Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease?

Since the 1980s, the cholinergic hypothesis of the pathogenesis of Alzheimer's disease has proven to be a strong stimulus to pharmacological strategies aimed at correcting the cognitive deficit by manipulating cholinergic neurotransmission. Among these strategies, the one based on acetylcholinesterase inhibition is currently the most extensively developed for the therapy of Alzheimer's disease. The inhibitors' mechanisms of action are complex, including changes in the release of acetylcholine, and modulation of acetylcholine receptors. Various clinical trials of various inhibitors have shown that, on the whole, their effects were modest and, in the case of some drugs, were associated with frequent adverse reactions. Among the conceivable reasons for the limited efficacy of these drugs, those related to the pharmacological target deserve particular attention. This review, therefore, focuses on the complex nature of the acetylcholine system, the alterations of acetylcholinesterase and muscarinic receptor signal transduction in Alzheimer's disease, and the involvement of other neurotransmitters.